Broensted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans

Article abstract of DOI:10.1021/jo402132p

Broensted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans has been developed. This method operates via the in situ formation of aminobenzylfuran, followed by its recyclization into the indole core. The method proved to be efficient for substrates possessing different functional groups, including -OMe, -CO₂Cy, and -Br. The resulting indoles can easily be transformed into diverse scaffolds, including 2,3- and 1,2-fused indoles, and indoles possessing an α,β-unsaturated ketone moiety at the C-2 position.

Full text of DOI:10.1021/jo402132p

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Article
Brönsted Acid-Catalyzed One-Pot Synthesis of
Indoles from o-Aminobenzyl Alcohols and Furans
Alexey Kuznetsov, Anton Makarov, Alexander E. Rubtsov, Alexander V. Butin, and Vladimir Gevorgyan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Nov 2013
Downloaded from http://pubs.acs.org on November 13, 2013
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Brönsted Acid-Catalyzed One-Pot Synthesis of Indoles from o-Aminobenzyl Alcohols and
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Furans
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9
Alexey Kuznetsov,1 Anton Makarov,2 Alexandr E. Rubtsov,2 Alexander V. Butin,*,2 and
Vladimir Gevorgyan*,1
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1Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago,
Illinois 60607-7061, United States
2Perm State University, 15 Bukireva Street, Perm, 614990, Russian Federation
alexander_butin@mail.ru
Corresponding author’s e-mail address:
vlad@uic.edu
Table of Contents/Abstract Graphic
R3
N
Ts
R3 = Ph, 59%
R2
R3
R2
O
Ph
O
10% TfOH
DCE, 80oC
OH
R3
R1
R1
N
N
NH
Ts
Ts
• one-pot
• gram scale
• 31 examples (41-96%)
R3 = Me, 69%
R3
Ph
O
R3
N
H
R3 = Me, 60%
Abstract
Brönsted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans
has been developed. This method operates via the in situ formation of aminobenzylfuran,
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followed by its recyclization into the indole core. The method proved to be efficient for
substrates possessing different functional groups, including -OMe, -CO2Cy, and -Br. The
resulting indoles can easily be transformed into diverse scaffolds, including 2,3- and 1,2-fused
indoles, and indole possessing an α,β-unsaturated ketone moiety at the C-2 position.
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1. Introduction
Low resonance energy of furan ring1 allows for its facile recyclization reactions into different
carbo-2 and heterocycles.3 Of particular interest, is recyclization reaction of furan into indole,
since valuable indole4 fragments can be obtained from readily available starting materials.5
Hence, a few reports document an intramolecular Pd-catalyzed arylative recyclization of furan-
containing aryl- or hetaryl halides A into indoles B (Scheme 1-1).3f,3g Recently, one of us
developed a Brönsted acid-mediated process for recyclization of furan derivatives 4 into indoles
3 (Scheme 1-2a). 6 This method needs preparation of furylmethyl aniline 4, which is
accomplished by condensation of benzyl alcohol 1 with furan 2. The recyclization step requires
the use of overstoichiometric amounts of HCl/AcOH, which substantially limits the scope of this
method. We thought that the development of more environmentally benign and general catalytic
method for recyclization of furan, which would exhibit wider substrate scope and potentially
would allow for a one-pot synthesis of indoles 3 directly from 1 and 2 is justified. Herein, we
wish to report general and efficient Brönsted acid-catalyzed synthesis of indoles from o-
aminobenzyl alcohols and furans, which features a one-pot protocol, wider substrate scope, and
higher functional group tolerance than the previously published two-step procedure (Scheme 1-
2b).
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Scheme 1. Methods for Recyclization of Furans into Indoles
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1. Pd-Catalyzed Recyclization of Furans into Indoles
O
R1
7
8
9
Br(I)
[Pd-cat]
Ar/
Ar/
Het
R2
R2
Het
PPh3, base
O
N
R3
N
R1
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R3
A
B
..
2. Bronsted Acid-Assisted Recyclization of Furans into Indoles
R2
R3
• 2 steps
O
TsOH
R2
HCl (excess)
or HCl/AcOH
• oversoichiometric
acid
• limited scope
R1
(a)
previous work
NH
Ts
4
R2
O
R3
R3
OH
R1
R1
H
O
N
NH
Ts
2
1
3
Ts
(b)
this work
• one-pot
• catalytic TfOH
• wider scope
10 mol% TfOH
one-pot
2. Results and Discussion
Optimization of the One-Pot Synthesis of Indole 3 from o-Aminobenzyl Alcohol 1a.
Recognizing that both steps of the sequence depicted in Scheme 1-2a proceed under electrophilic
conditions, we hypothesized that finding conditions for formation of indole 3 directly from
aminobenzyl alcohol 1 and 2-methylfuran 2 is feasible. To this end, different Lewis acid
catalysts were first screened for the one-pot recyclization of 1a and 2a into 3aa (Table 1). Thus,
employment of FeCl3 resulted in efficient formation of intermediate 4aa with only traces of
target indole 3aa produced (entry 1). Employment of copper, indium, and silver triflates was
more efficient for the second step leading to better ratios of 3aa/4aa (entries 2-4). Use of
Sc(OTf)3 resulted in nearly complete conversion of starting materials into indole 3aa (entry 5).
In order to verify whether Sc(OTf)3 is the true catalyst in this recyclization reaction, or if it is
catalyzed by the Brönsted acid7 (TfOH) produced by a hydrolysis of Sc(OTf)3 during the first
dehydrocondensation step, the following test experiments were performed. First, addition of
activated molecular sieves, which scavenged the forming water and thus suppressed the
hydrolysis of Sc(OTf)3, resulted in much more sluggish recyclization reaction, producing
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intermediate 4aa as a major product (entry 6). Moreover, addition of 30 mol% of a proton
scavenger 2,4,6-tritertbutylpyrimidine (TTBP)8 had a similar inhibition effect on the second step
of the reaction (entry 7). Finally, addition of both water- and a proton scavengers completely
shut down the recyclization step, thus producing furylmethyl aniline 4aa as a single reaction
product (entry 8). These results unambiguously demonstrate that TfOH is the true catalyst of the
recyclization step (4aa→3aa). Consequently, we examined several other Brönsted acids in the
recyclization reaction of 1a and 2a into 3aa. It was found that employment of HNTf2, HCl, and
CF3CO2H produced only intermediate 4aa in low to moderate yields (entries 9-12). Use of
H2SO4 and TsOH gave mixtures of indole 3aa and furyl aniline derivative 4aa (entries 13, 14).
Remarkably, in the presence of MsOH and TfOH indole 3aa was produced in 87% and 95%
yields, respectively (entries 15, 16). The following optimization with TfOH as the catalyst
(entries 17-19) revealed optimal conditions for this Brönsted acid-catalyzed transformation
(entry 18), which allowed for a facile and complete conversion of 1a and 2a into indole 3aa.
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Table 1. Optimization of the One-Pot Synthesis of Indole 3 from o-Aminobenzyl Alcohol
5
6
1aa
7
8
9
2 equiv
Ph
Ph
OH
Ph
O
O
O
2a
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catalyst
DCE, 80oC
N
NH
Ts
NH
Ts
1a
4aa
3aa
Ts
entry
catalyst
time, h
yield 3 (4), %b
1
2
3
4
10% FeCl3
10% Cu(OTf)2
10% In(OTf)3
10% AgOTf
10% Sc(OTf)3
10% Sc(OTf)3
10% Sc(OTf)3
10% Sc(OTf)3
10% HNTf2
10% HCl
12
12
2
<5 (91)
53 (38)
87 (10)
80 (13)
92 (<1)
29 (61)
22 (70)
-- (94)
-- (68)
-- (38)
-- (21)
-- (58)
39 (50)
41 (48)
87 (0)
1
5
12
24
24
24
12
12
12
12
12
12
4
6c
7d
8c,d
9
10e
11e
12
13
14
15
16
17
18f
19g
100% HCl
10% CF3COOH
10% H2SO4
10% TsOH
10% MsOH
10% TfOH
5% TfOH
1
4
1
1
95 (0)
91 (0)
94 (0)
10% TfOH
10% TfOH
73 (0)
aReaction conditions: o-Aminobenzyl alcohol 1a (0.2 mmol), 2-
methylfuran 2a (2 equiv, 0.4 mmol, 35.8 µL), and catalyst were
stirred in DCE (0.7 mL, 0.3 M) at 80oC. The progress of the reaction
was monitored by TLC. bNMR Yield. cIn the presense of 50 mg
molecular sieves 4Å. dIn the presence of 30 mol% 2,4,6-
e
f
tritertbutylpyrimidine. 4M HCl in dioxane was used. 1.5 equiv of
2-methylfuran was used. g1.2 equiv of 2-methylfuran was used.
Scope of Furans in the One-Pot Synthesis of Indoles. With the optimized conditions in
hand, we explored the generality of this one-pot recyclization reaction. First, the scope of
recyclization reaction of aminoalcohol 1a with different furans 2 was examined (Table 2). Thus,
2-alkyl- and 2-cycloalkylfurans 2a-d were smoothly converted into the corresponding indoles
3ab-3ad in good to excellent yields (entries 1-5). We also showed that recyclization reaction
could be easily scaled up to a gram-scale synthesis of indole 3aa (entry 2). Different 2-arylfurans
2e-m, possessing MeO-, Br-, F-, and CF3- groups were also efficiently transformed into indoles
3ae-3am (entries 6-14). Remarkably, it was found that sterically bulky 2-arylfurans 2g-2i are
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also competent reactants in this reaction providing the corresponding indoles 3ag-3ai in good
yields (entries 8-10). Furans 2n and 2o, possessing an ester group in a side chain, recyclized
uneventfully producing indoles 3an and 3ao in 61% and 68% yield, respectively (entry 15-16).
Likewise, 2,3-disubstituted furans, such as 2,3-dimethylfuran 2p and 4,5,6,7-
tetrahydrobenzofuran 2q, produced the corresponding indoles 3ap and 3aq in high yields (entries
17-18). Benzofuran 2r also underwent recyclization to produce benzylphenoloindole derivative
3ar in moderate yield (entry 19). However, when C-4 substituted menthofuran 2s was used, no
recyclization product 3as was formed (entry 20). Noteworthy, not only these catalytic one-pot
conditions are more convenient experimentally, but they also exhibit wider substrate scope.
Thus, attempts on recyclization of intermediate 4ae under previously developed conditions (HCl-
EtOH)6 in 12 hours produced no detectable amounts of indole 3ae. Moreover, recyclization of
furylmethyl aniline 4ao using HCl-EtOH produced transesterified indole 3an.9
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Table 2. Scope of Furans in the One-Pot Synthesis of Indoles from o-Aminobenzyl Alcohola
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8
Ph
Ph
R
O
10% TfOH
OH
R
DCE (0.3M)
80oC, 1 h
O
N
Ts
NH
Ts
2
1a
1.5 equiv
3
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entry
furan
O
product
Ph
3, yield
O
R
R
N
Ts
1
2
2a: R = Me
2a: R = Me
2b: R = n-Bu
2c: R = Cpent
2d: R = Cy
3aa: R = Me
90%
83%
95%
93%
75%
b
3aa: R = Me
3ab: R = n-Bu
3ac: R = Cpent
3ad: R = Cy
3
4
5
Ph
O
R
R
O
N
Ts
c
6
2e: R = H
2f: R = 2-OMe
2g: R = 2-CF
2h: R = 2,3-benzo
2i: R = 2,4,6-triiPr
2j: R = 4-CF3
2k: R = 4-F
2l: R = 4-Br
2m: R = 4-OMe
87%
85%
56%
53%
48%
60%
83%
70%
56%
3ae: R = H
3af: R = 2-OMe
3ag: R = 2-CF
3ah: R = 2,3-benzo
3ai: R = 2,4,6-triiPr
3aj: R = 4-CF3
3ak: R = 4-F
3al: R = 4-Br
3am: R = 4-OMe
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8
9
10
11
12
13
14
3
3
Ph
O
CO2R
( )2
CO2R
( )2
O
N
Ts
15
16
2n: R = Et
2o: R = Cy
3an: R = Et
3ao: R = Cy
61%
68%
Ph
O
O
N
Ts
17
18
19
2p
3ap
87%
70%
45%
Ph
O
O
N
Ts
2q
3aq
Ph
OH
O
N
Ts
2r
3ar
Ph
O
O
N
d
Ts
20
2s
3as
0%
aReaction conditions: o-Aminobenzyl alcohol 1a (0.5 mmol),
furan 2 (1.5 equiv, 0.75 mmol), and TfOH (10 mol%, 4.5 µL)
were stirred in DCE (1.6 mL, 0.3 M) at 80oC. The progress of the
reaction was monitored by TLC. bReaction was performed on 4.0
c
mmol scale in a pressure tube. Reaction mixture (entries 6-14)
was heated at 110oC for 2h. dFurylmethyl aniline intermediate
4ar was isolated in 95% yield.
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Scope of o-Aminobenzyl Alcohols in the One-Pot Synthesis of Indoles. Next, the scope of
the reaction with regard to the R1 substituent at the α-position of aminobenzyl alcohol 1 was
examined (Table 3, entries 1-8). It was found that alkyl-substituted benzyl alcohols, such as
methyl-, iso-propyl-, tert-butyl-, and cyclohexyl-, can be easily transformed into indoles 3ba-3ea
in good to excellent yields (entries 1-4). Likewise, aryl-containing aminoalcohols, possessing F-,
Me-, and MeO- groups efficiently cyclized into indoles 3fa-3ha (entries 5-7). Recyclization of 2-
thienyl-substituted benzyl alcohol 1i produced the corresponding indole 3ia in 41% yield (entry
8).
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Next, aminoalcohols possessing different substituents at the aniline ring were tested in this
recyclization reaction (Table 3, entries 9-14). Thus, reaction of 4,5-difluoro- and 4,5-
dimethoxybenzyl alcohols 1j and 1k led to the formation of indoles 3ja and 3ka in good yields
(entries 9-10). 5-Trifluoromethylbenzyl alcohol 1l and 4-bromobenzyl alcohol 1m provided
indoles 3la and 3ma in good yields, as well (entries 11-12). It is worth mentioning that 6-methyl
aminoalcohol 1n was not efficient in this reaction (entry 13), whereas recyclization of 6-chloro
aminoalcohol 1o provided N-detosylated indole 3oa in reasonable yield (entry 14).
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Table 3. Variation of Substituents at α-Position and at Aniline Phenyl Ring of o-
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8
Aminobenzyl Alcoholsa
R1
R1
R2-4
R2-4
10% TfOH
9
OH
O
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DCE (0.3M)
80oC, 1 h
O
N
Ts
NH
Ts
2a
1.5 equiv
1
3
3, yieldb
entry
aminoalcohol
R1
product
R1
O
OH
N
Ts
NH
Ts
11 1b: R1 = Me
3ba: R1 = Me
88%1
76%
63%
83%
72%
60%
71%
41%
2
3
4
5
6
7
8
1c: R1
1d: R1
1e: R1
=
=
=
iPr
tBu
Cy
3ca: R1
3da: R1
3ea: R1
=
=
=
iPr
tBu
Cy
1f: R1 = 4-FC6H4-
1g: R1 = 4-MeC6H4-
1h: R1 = 4-MeOC6H4-
1i: R1 = 2-thienyl
3fa: R1 = 4-FC6H4-
3ga: R1 = 4-MeC6H4-
3ha: R1 = 4-MeOC6H4-
3ia: R1 = 2-thienyl
Ph
Ph
O
R2
R3
R2
R3
OH
N
NH
Ts
Ts
19
10
11
12
1j: R2 = R3 = F
3ja: R2 = R3 = F
79%
60%
63%
61%1
1k: R2 = R3 = OMe
1l: R2 = H, R3 = CF3
1m: R2 = Br, R3 = H
3ka: R2 = R3 = OMe
3la: R2 = H, R3 = CF3
3ma: R2 = Br, R3 = H
Ph
Ph
O
OH
N
NH
R4 Ts
G
R4
13
1n: R4 = Me
141 1o: R4 = Cl
3na: R4 = Me, G = Ts
3oa: R4 = Cl, G = H
traces
58%1
aReaction conditions: o-Aminobenzyl alcohol 1 (0.5 mmol), 2-
methylfuran 2a (1.5 equiv, 0.75 mmol, 67.1 µL), and TfOH (10
mol%, 4.5 µL) were stirred in DCE (1.6 mL, 0.3 M) at 80oC. The
progress of the reaction was monitored by TLC.
Further Modifications of the Obtained Indoles. After establishing the scope of this one-
pot recyclization reaction, we then performed several transformations that highlight the utility of
the synthesized indoles. Thus, the formed indole 3ae, upon reduction of its carbonyl group into
alcohol group and subsequent Friedel-Crafts-type cyclization, was smoothly converted into
tetracyclic indole core 5 (Scheme 2).10 Removal of the tosyl group with sodium naphthalenide,11
produced N–H indole 6, which upon oxidation with DDQ, furnished α,β-unsaturated ketone 7.
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Alternatively, upon reaction with excess Mg in methanol,12 the tosyl group in indole 3aa was
efficiently removed with simultaneous reduction of the carbonyl group to produce alcohol 8. The
latter, upon mesylation and subsequent intramolecular N-alkylation,13 was easily converted into
dihydropyrroloindole 9, an important motif found in a number of drug candidates and natural
products.14
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Scheme 2. Further Modifications of the Obtained Indoles
Ph
O
Ph
O
DDQ
R
R
N
N
7
6
H
H
Na•naphth
DME, -60oC
R = Me, 83%
R = Me, 72%
Ph
O
R
1. LiAlH4
R
2. BF3•Et2O
N
Ts
3ae, R = Ph
3aa, R = Me
N
Ts
5
R = Ph, 59%
(over 2 steps)
Mg/MeOH
Ph
N
Ph
OH
1. MsCl/Py
R
2. NaH/DMF
N
H
9
8
R
R = Me, 79%
R = Me, 87%
3. Conclusion
In summary, we developed an efficient one-pot Brönsted acid-catalyzed method for synthesis
of indoles from o-aminobenzyl alcohols and furans. This method features initial formation of
aminobenzylfuran, followed by its recyclization into indole possessing ethyl ketone moiety. This
method proved to have wider substrate scope and higher functional group tolerance than the
previously reported two-step procedure. The formed indoles can be further transformed into
valuable 2,3- and 1,2-fused indoles, and into indoles possessing an α,β-unsaturated ketone
moiety.
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4. Experimental Section
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General Information. Column chromatography was carried out employing Silicycle Silica-P
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flash silica gel (40-63 µm). Precoated silica gel plates F-254 were used for thin-layer analytical
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chromatography (TLC). Chemical shifts for H and 13C nuclear magnetic resonance (NMR)
spectra were reported in parts per million (ppm, δ). HRMS analyses were performed on either
Micromass 70-VSE mass spectrometer by using electron ionization (EI) technique with Spector
analyzer or by using electrospray ionization (ESI) with time-of-flight (TOF) analyzer. Anhydrous
solvents purchased from suppliers were additionally purified on solvent purification system
and/or stored over calcium hydride/molecular sieves. 2-Aryl/alkylfurans, if not commercially
available, were synthesized from 2-bromofuran.15
Synthesis of Starting Materials. 2-(N-tosylamino)benzaldehyde ab1 was prepared as
described.16
1. TsCl/Py
OH
NH2
O
2. PCC
NH
Ts
ab1
To a solution of 2-aminobenzyl alcohol (6.2 g, 50.0 mmol) and pyridine (1.2 equiv, 4.8 mL, 60.0
mmol) in CHCl3 (165 mL), TsCl (0.98 equiv, 9.3 g, 49.0 mmol) in CHCl3 (50 mL) was added
dropwise at room temperature. The reaction mixture was stirred for 3 h and then quenched with
water (50 mL). The organic phase was separated, washed with water, dried over Na2SO4, and
concentrated to give the 2-(N-tosylamino)benzyl alcohol (13.5 g, 48,6 mmol, 97%), which was
used directly in the next step.
To a stirred suspension of PCC (1.5 equiv, 15.7 g, 72.9 mmol) in CH2Cl2 (240 mL), a
solution of the 2-(N-tosylamino)benzyl alcohol in CH2Cl2 (360 mL) was added dropwise at room
temperature. The mixture was stirred for 3 h. The liquid was decanted from the solid, and the
remaining solid was washed several times with Et2O (3x100 mL). The combined organic
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fractions were passed through a short pad of silica gel. The silica gel was additionally washed
with CH2Cl2 (3x100 mL) and the combined organic solutions were evaporated to give the crude
product. The product was recrystallized from CHCl3/EtOH (1/5, 100 mL) to yield aldehyde ab1
as a white-yellow solid (11.2 g, 40.8 mmol, 84%), which was used directly in the synthesis of
alcohols 1.
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General procedure for the synthesis of 2-(N-tosylamino)-4,5-difluorobenzaldehyde ab2, 2-
(N-tosylamino)-4-trifluoromethylbenzaldehyde ab3, 2-(N-tosylamino)-5-bromobenzaldehyde
ab4, and 2-(N-tosylamino)-3-chlorobenzaldehyde ab5.17
O
1. TsCl/Na2CO3
ab2, R = 4,5-diF
ab3, R = 4-CF3
ab4, R = 5-Br
ab5, R = 3-Cl
OH
NH2
R = EWG
O
R
R
2. LAH
3. PCC
NH
Ts
To a solution of a proper 2-aminobenzoic acid (5 mmol) and Na2CO3 (2.5 equiv) in distilled
water (0.4 M) heated to 60 °C, TsCl (1.25 equiv) was added during the course of 15 min. The
mixture was then heated to 85 °C and stirred at this temperature for 3 h. The hot mixture was
then cooled down and mixed with ice. HCl (6 N) was added dropwise to the resulted mixture
until slightly acidic pH (caution: CO2 evolution!). The resulted white suspension was extracted
with EtOAc (3x10 mL), and combined organic solutions were additionally washed with HCl (1
N), dried over Na2SO4, and evaporated to give the 2-(N-tosylamino)benzoic acid. The crude
product was used directly in the next step.
Under a nitrogen atmosphere, to an ice-cooled stirred suspension of LiAlH4 (2.0 equiv) in
THF (0.2M), a solution of 2-(N-tosylamino)benzoic acid in minimum amount of THF was added
dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 3 h.
After completion of the reaction (determined by TLC, eluent hexanes:EtOAc = 2:1), the reaction
mixture was cooled down (ice bath) and saturated aqueous NH4Cl (2.0 mL) was added dropwise
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(caution: H2 evolution!). The resulting sluggish mixture was filtered through Celite® and
concentrated. The crude product was used directly in the next step.
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The resulted alcohol was oxidized to aldehyde using PCC as described earlier. The obtained
aldehydes ab2-ab5 were used directly in the synthesis of alcohols 1.
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General procedure for the synthesis of 2-(N-tosylamino)-4,5-dimethoxybenzaldehyde ab6
and 2-(N-tosylamino)-3-methylbenzaldehyde ab7.18
O
1. MeOH/H2SO4
2. TsCl/Py
OH
O
ab6, R = 4,5-diMeO
ab7, R = 3-Me
R
R
3. LAH
4. PCC
NH2
R = EDG
NH
Ts
A solution of a proper 2-aminobenzoic acid (5 mmol), methanol (10 mL), and concentrated
H2SO4 (2 mL) was heated under reflux for 24 h. The reaction mixture was cooled down,
concentrated, poured into ice, neutralized with solid Na2CO3 (caution: CO2 evolution!), and
extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with water,
saturated aqueous NaHCO3, dried over Na2SO4, and concentrated to provide a crude methyl 2-
aminobenzoate, which was used directly in the next step.
To a solution of crude methyl 2-aminobenzoate and pyridine (3 equiv) in CH2Cl2 (10 mL), a
solution of TsCl (0.98 equiv) in CH2Cl2 (5 mL) was added dropwise at room temperature. The
reaction mixture was stirred for 3 h and then quenched with water (10 mL). The organic layer
was separated, washed with water, dried over Na2SO4, and concentrated. The crude product was
used directly in the next step.
Reduction of methyl ester with LiAlH4 and subsequent oxidation of the resulted alcohol to
aldehyde with PCC was done as described earlier. The obtained aldehydes ab6-ab7 were used
directly in the synthesis of alcohols 1.
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General procedure for the synthesis of 2-(N-tosylamino)benzyl alcohols 1 from 2-(N-
tosylamino)benzaldehydes ab.
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R2
R2Li or
OH
O
R1
R1
R2MgCl(Br)
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NH
Ts
NH
Ts
1
ab
An oven dried, argon flushed 25 mL flask was loaded with 2-(N-tosylamino)benzaldehyde
o
ab (1.0 mmol) and THF (8.0 mL, 0.125 M). The flask was cooled to –78 C and a solution of
R2Li/R2MgCl(Br) (2.2 mmol, 2.2 equiv) was added dropwise. The resulting mixture was allowed
to warm up to 0 oC, and saturated NH4Cl (5 mL) was added. The organic layer was separated and
the water layer was washed with ethyl acetate (2x5 mL). The combined organic solutions were
dried over Na2SO4 and the solvents were evaporated. The resulted crude product was purified by
recrystallization from iPrOH to give pure alcohol 1 as a white solid.
N-(2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide (1a) was obtained from
aldehyde ab1 and PhLi, 332 mg (94%), Rf = 0,09 (hexanes/EtOAc = 4/1). The spectral data
matched that of the previously synthesized material.6 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H),
7.48-7.46 (m, 3H), 7.32-7.30 (m, 3H), 7.23 (t, J = 7.3 Hz, 1H), 7.17-7.14 (m, 4H), 7.02 (t, J = 7.7
13
Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 5.67 (s, 1H), 2.69 (broad s, 1H), 2.36 (s, 3H). C NMR (125
MHz, CDCl3) δ 143.6, 141.0, 136.6, 135.8, 133.1, 129.5, 129.0 (2C), 128.6, 127.9, 127.2, 126.3,
124.6, 122.1, 74.7, 21.5. HRMS (EI+) calcd. for C20H19NO3S [M]+: 353.1086, measured:
353.1087.
N-(2-(1-hydroxyethyl)phenyl)-4-methylbenzenesulfonamide (1b) was obtained from aldehyde
ab1 and MeLi, 255 mg (88%), Rf = 0,18 (hexanes/EtOAc = 4/1). The spectral data matched that
of the previously synthesized material.19 1H NMR (500 MHz, CDCl3) δ 8.51 (broad s, 1H), 7.68-
7.67 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.22-7.20 (m, 2H), 7.17 (dt, J = 7.3, 1.7 Hz, 1H), 7.09-
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7.02 (m, 2H), 4.84 (q, J = 6.6 Hz, 1H), 2.68 (broad s, 1H), 2.36 (s, 3H), 1.34 (d, J = 6.6 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 143.7, 136.9, 135.7, 134.0, 129.6, 128.5, 127.1, 127.0, 124.6,
121.8, 69.8, 22.8, 21.5. HRMS (EI+) calcd. for C15H17NO3S [M]+: 291.0929, measured:
291.0935.
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N-(2-(1-hydroxy-2-methylpropyl)phenyl)-4-methylbenzenesulfonamide (1c) was obtained
i
1
from aldehyde ab1 and PrMgCl, 213 mg (67%), Rf = 0,21 (hexanes/EtOAc = 4/1). H NMR
(500 MHz, CDCl3) δ 8.48 (broad s, 1H), 7.67-7.66 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 7.21-7.15
(m, 3H), 7.00-6.95 (m, 2H), 4.23 (d, J = 9.0 Hz, 1H), 2.70 (broad s, 1H), 2.36 (s, 3H), 1.66 (m,
13
1H), 1.00 (d, J = 6.6 Hz, 3H), 0.43 (d, J = 6.8 Hz, 3H). C NMR (125 MHz, CDCl3) δ 143.7,
136.8, 135.8, 132.0, 129.5, 129.2, 128.3, 127.1, 123.9, 121.3, 81.3, 33.4, 21.5, 19.4, 19.2. HRMS
(EI+) calcd. for C17H21NO3S [M]+: 319.1242, measured: 319.1245.
N-(2-(1-hydroxy-2,2-dimethylpropyl)phenyl)-4-methylbenzenesulfonamide (1d) was obtained
t
1
from aldehyde ab1 and BuMgCl, 209 mg (63%), Rf = 0,23 (hexanes/EtOAc = 4/1). H NMR
(500 MHz, CDCl3) δ 8.86 (broad s, 1H), 7.76-7.74 (m, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.24-7.23
(m, 2H), 7.14 (m, 1H), 6.99-6.93 (m, 2H), 4.51 (s, 1H), 2.53 (broad s, 1H), 2.38 (s, 3H), 0.98 (s,
9H). 13C NMR (125 MHz, CDCl3) δ 143.6, 137.1, 136.6, 130.5, 129.6, 128.4, 128.1, 127.3,
122.6, 119.4, 84.0, 37.3, 26.3, 21.5. HRMS (EI+) calcd. for C18H23NO3S [M]+: 333.1399,
measured: 333.1404.
N-(2-(cyclohexyl(hydroxy)methyl)phenyl)-4-methylbenzenesulfonamide (1e) was obtained
1
from aldehyde ab1 and CyMgBr, 305 mg (85%), Rf = 0,20 (hexanes/EtOAc = 4/1). H NMR
(500 MHz, CDCl3) δ 8.62 (broad s, 1H), 7.70-7.69 (m, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.23-7.17
(m, 3H), 7.00-6.97 (dt, J = 7.5, 1.1 Hz, 1H), 6.92 (dd, J = 7.7, 1.5 Hz, 1H), 4.29 (d, J = 9.0 Hz,
1H), 2.65 (broad s, 1H), 2.37 (s, 3H), 2.05 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 1.48 (m, 1H),
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1.30 (m, 1H), 1.14-1.01 (m, 2H), 0.95-0.89 (m, 2H), 0.79 (m, 1H), 0.67 (m, 1H). 13C NMR (125
MHz, CDCl3) δ 143.7, 137.0, 135.9, 131.2, 129.6, 129.3, 128.3, 127.1, 123.6, 120.9, 80.7, 42.5,
29.6, 29.5, 26.1, 25.6, 25.4, 21.5. HRMS (EI+) calcd. for C20H25NO3S [M]+: 359.1555,
measured: 333.1558.
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N-(2-((4-fluorophenyl)(hydroxy)methyl)phenyl)-4-methylbenzenesulfonamide
(1f)
was
obtained from aldehyde ab1 and 4-FC6H4MgBr, 248 mg (67%), Rf = 0,13 (hexanes/EtOAc =
1
4/1). H NMR (500 MHz, CDCl3) δ 8.06 (broad s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.44-7.43 (m,
2H), 7.21 (dt, J = 8.1, 1.5 Hz, 1H), 7.13-7.12 (m, 2H), 7.10-7.08 (m, 2H), 7.02 (dt, J = 7.5, 0.7
Hz, 1H), 6.94-6.90 (m, 3H), 5.72 (s, 1H), 3.10 (broad s, 1H), 2.38 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 163.2 (d, JC-F = 246.0 Hz), 143.7, 136.9 (d, JC-F = 2.8 Hz), 136.4, 135.7, 133.0, 129.5,
129.1 (d, JC-F = 3.7 Hz), 127.9 (d, JC-F = 8.3 Hz), 127.0, 124.7, 122.1, 115.3 (d, JC-F = 22.2 Hz),
74.1, 21.5. HRMS (EI+) calcd. for C20H18NO3SF [M]+: 371.0991, measured: 371.0986.
N-(2-(hydroxy(p-tolyl)methyl)phenyl)-4-methylbenzenesulfonamide (1g) was obtained from
1
aldehyde ab1 and 4-MeC6H4MgBr, 256 mg (70%), Rf = 0,12 (hexanes/EtOAc = 4/1). H NMR
(500 MHz, CDCl3) δ 8.08 (broad s, 1H), 7.49-7.47 (m, 3H), 7.22 (m, 1H), 7.15-7.10 (m, 4H),
7.04-7.00 (m, 3H), 6.93 (d, J = 7.7 Hz, 1H), 5.62 (d, J = 3.1 Hz, 1H), 2.81 (d, J = 3.5 Hz, 1H),
2.39 (s, 3H), 2.37 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 143.5, 138.0, 137.5, 136.5, 135.8,
133.1, 129.4, 129.3, 128.9, 128.8, 127.1, 126.2, 124.5, 121.9, 74.5, 21.5, 21.1. HRMS (EI+)
calcd. for C21H21NO3S [M]+: 367.1242, measured: 367.1240.
N-(2-(hydroxy(4-methoxyphenyl)methyl)phenyl)-4-methylbenzenesulfonamide
(1h)
was
obtained from aldehyde ab1 and 4-MeOC6H4MgBr, 321 mg (84%), Rf = 0,06 (hexanes/EtOAc =
1
4/1). H NMR (500 MHz, CDCl3) δ 8.19 (broad s, 1H), 7.47-7.45 (m, 3H), 7.19 (m, 1H), 7.13-
7.11 (m, 2H), 7.05-6.99 (m, 3H), 6.91 (d, J = 7.7 Hz, 1H), 6.80-6.78 (m, 2H), 5.59 (broad s, 1H),
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3.79 (s, 3H), 3.11 (m, 1H), 2.37 (s, 3H). C NMR (125 MHz, CDCl3) δ 159.1, 143.5, 136.5,
5
6
7
8
135.7, 133.2, 129.4, 128.9, 128.7, 127.6, 127.1, 124.4, 121.8, 113.9, 74.3, 55.2, 21.4. HRMS
(EI+) calcd. for C21H21NO4S [M]+: 383.1191, measured: 383.1194.
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N-(2-(hydroxy(thiophen-2-yl)methyl)phenyl)-4-methylbenzenesulfonamide (1i) was obtained
from aldehyde ab1 and thiophen-2-yl lithium (prepared by mixing 2-bromothiophene with 1.1
o
1
equiv of n-BuLi in THF at -78 C), 341 mg (95%), Rf = 0,15 (hexanes/EtOAc = 4/1). H NMR
(500 MHz, CDCl3) δ 8.10 (broad s, 1H), 7.49-7.48 (m, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.26-7.21
(m, 2H), 7.15-7.13 (m, 2H), 7.10-7.03 (m, 2H), 6.87 (dd, J = 5.1, 3.5 Hz, 1H), 6.59 (m, 1H), 5.93
(m, 1H), 3.41 (m, 1H), 2.43 (s, 3H). 13C NMR (125 MHz, acetone-d6) δ 148.7, 144.9, 138.3,
137.4, 134.7, 130.8, 129.9 (2C), 128.4, 126.4, 125.6, 125.3, 121.9, 72.6, 21.8. HRMS (EI+)
calcd. for C18H17NO3S2 [M]+: 359.0650, measured: 359.0648.
N-(4,5-difluoro-2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide (1j) was
1
obtained from aldehyde ab2 and PhLi, 303 mg (78%), Rf = 0,19 (hexanes/EtOAc = 4/1). H
NMR (500 MHz, CDCl3) δ 7.46-7.45 (m, 2H), 7.30-7.26 (m, 4H), 7.18-7.16 (m, 2H), 7.09-7.08
(m, 2H), 6.66 (dd, J = 10.8, 8.6 Hz, 1H), 5.53 (s, 1H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 149.5 (dd, JC-F = 249.7, 13.9 Hz), 147.1 (dd, JC-F = 247.8, 12.9 Hz), 144.3, 140.4, 135.8, 131.8
(JC-F = 6.5 Hz), 131.0, 129.8, 128.8, 128.2, 127.1, 126.3, 117.6 (JC-F = 19.4 Hz), 112.2 (JC-F
=
21.3 Hz), 73.2, 21.5. HRMS (EI+) calcd. for C20H17NO3SF2 [M]+: 389.0897, measured:
389.0895.
N-(4,5-dimethoxy-2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide (1k) was
1
obtained from aldehyde ab6 and PhLi, 313 mg (76%), Rf = 0,10 (hexanes/EtOAc = 2/1). H
NMR (500 MHz, CDCl3) δ 7.53-7.51 (m, 2H), 7.31-7.27 (m, 4H), 7.21-7.19 (m, 2H), 7.15-7.13
(m, 2H), 6.83 (s, 1H), 6.45 (s, 1H), 5.62 (d, J = 3.3 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 2.73
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(broad s, 1H), 2.41 (s, 3H). C NMR (125 MHz, CDCl3) δ 148.7, 146.8, 143.8, 141.6, 136.3,
129.6, 128.7, 128.5, 127.7, 127.4, 126.3, 111.5, 108.6, 73.0, 55.9, 21.5. HRMS (EI+) calcd. for
C22H23NO5S [M]+: 413.1297, measured: 413.1294.
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N-(2-(hydroxy(phenyl)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzenesulfonamide (1l)
was obtained from aldehyde ab3 and PhLi, 341 mg (81%), Rf = 0,16 (hexanes/EtOAc = 4/1). 1H
NMR (500 MHz, CDCl3) δ 8.34 (broad s, 1H), 7.72 (s, 1H), 7.45-7.44 (m, 2H), 7.33-7.31 (m,
3H), 7.26-7.24 (d, J = 8.1 Hz, 1H), 7.18-7.14 (m, 4H), 7.07 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H),
3.18 (s, 1H), 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 144.2, 140.3, 136.4, 136.0, 135.7,
131.1 (q, JC-F = 32.4 Hz), 129.7, 129.5, 128.8, 128.2, 127.2, 126.2, 123.5 (q, JC-F = 272.8 Hz),
120.8, 118.0, 74.5, 21.5. HRMS (EI+) calcd. for C21H18NO3SF3 [M]+: 421.0960, measured:
421.0940.
N-(4-bromo-2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide
(1m)
was
1
obtained from aldehyde ab4 and PhLi, 401 mg (93%), Rf = 0,12 (hexanes/EtOAc = 4/1). H
NMR (500 MHz, CDCl3) δ 8.02 (broad s, 1H), 7.45-7.43 (m, 2H), 7.33-7.32 (m, 5H), 7.16-7.14
(m, 4H), 7.07 (d, J = 1.8 Hz, 1H), 5.61 (s, 1H), 2.96 (broad s, 1H), 2.39 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 143.9, 140.2, 136.1, 135.1, 134.6, 131.8, 131.7, 129.7, 128.8, 128.2, 127.1,
126.3, 123.5, 117.7, 74.2, 21.5. HRMS (ES+) calcd. for C20H18NO3SBrNa [M+Na]+: 454.0088,
measured: 454.0090.
N-(2-(hydroxy(phenyl)methyl)-6-methylphenyl)-4-methylbenzenesulfonamide
(1n)
was
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obtained from aldehyde ab7 and PhLi, 235 mg (64%), Rf = 0,08 (hexanes/EtOAc = 4/1). H
NMR (500 MHz, CDCl3) δ 7.63-7.61 (m, 2H), 7.33-7.27 (m, 5H), 7.21-7.19 (m, 2H), 7.11-7.07
(m, 2H), 6.94 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 5.96 (s, 1H), 3.11 (broad s, 1H), 2.45 (s, 3H),
1.94 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 144.1, 142.8, 142.5, 137.1, 137.0, 132.0, 130.7,
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129.8, 128.3, 128.0, 127.3, 127.2, 127.1, 126.5, 71.3, 21.6, 18.4. HRMS (EI+) calcd. for
C21H21NO3S [M]+: 367.1242, measured: 367.1241.
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(1o)
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obtained from aldehyde ab5 and PhLi, 232 mg (60%), Rf = 0,10 (hexanes/EtOAc = 4/1). H
NMR (500 MHz, CDCl3) δ 7.55-7.54 (m, 2H), 7.37-7.35 (m, 2H), 7.32-7.21 (m, 6H), 7.14-7.13
(m, 2H), 6.67 (broad s, 1H), 6.61 (s, 1H), 3.78 (broad s, 1H), 2.42 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 146.4, 144.5, 142.9, 135.6, 132.0, 130.2, 129.6, 129.2, 129.0, 128.6, 128.1, 127.6,
127.0, 126.1, 70.2, 21.6. HRMS (EI+) calcd. for C20H18NO3SCl [M]+: 387.0696, measured:
387.0697.
One-Pot Synthesis of Indoles from o-Aminobenzyl Alcohols. Optimization of the One-Pot
Synthesis of Indoles from o-Aminobenzyl Alcohols (Table 1). In a 1 mL Wheaton microreactor
vial, equipped with a Teflon pressure cap, a mixture of o-aminobenzyl alcohol 1a (0.1 mmol,
35.3 mg), 2-methylfuran 2a (0.2 mmol, 2 equiv, 18 µL), catalyst, and DCE (0.4 mL, 0.25M) was
stirred at 80oC. The progress of the reaction was monitored by TLC (eluent hexanes:EtOAc =
4:1). After completion, the reaction mixture was filtered through Celite®, the solvent was
evaporated and crude product was analyzed by 1H NMR.
General procedure for one-pot synthesis of indoles from aminobenzylalcohols and furans. In
a 3 mL Wheaton microreactor vial, to a stirred suspension of aminobenzylalcohol 1 (0.4 mmol)
and furan 2 (0.6 mmol, 1.5 equiv) in DCE (1.3 mL, 0.3M), triflic acid (0.04 mmol, 10 mol%, 3.6
µL) was added. The microreactor was capped with a Teflon pressure cap and placed into pre-
heated (80oC) aluminum block. The resulted solution was stirred for 1-2 h at this temperature.
After completion of the reaction (determined by TLC, eluent hexanes:EtOAc = 4:1),
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microreactor, containing product 3, was cooled down and the reaction mixture was diluted with
1.5 mL of hexanes. The product was purified using flash silica gel column chromatography.
N-tosyl-2-(3-oxobutyl)-3-phenylindole (3aa): 150 mg (90%), yellow oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,42 (hexanes/EtOAc = 4/1). The spectral data matched that of the
previously synthesized material.6 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 7.65
(d, J = 8.1 Hz, 2H), 7.46-7.43 (m, 2H), 7.39-7.28 (m, 5H), 7.23-7.18 (m, 3H), 3.35 (t, J = 7.7 Hz,
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2H), 2.94 (t, J = 7.7 Hz, 2H), 2.34 (s, 3H), 2.14 (s, 3H). C NMR (125 MHz, CDCl3) δ 207.3,
144.9, 136.7, 136.3, 135.5, 132.6, 130.6, 129.9, 129.8, 128.7, 127.7, 126.4, 124.7, 124.4, 123.9,
119.5, 115.2, 44.7, 29.8, 21.6, 21.3. HRMS (EI+) calcd. for C25H23NO3S [M]+: 417.1399,
measured: 417.1388.
N-tosyl-2-(3-oxoheptyl)-3-phenylindole (3ab): 174 mg (95%), yellow oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,42 (hexanes/EtOAc = 4/1). 1H NMR (500 MHz, CDCl3) δ 8.25 (d,
J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.45-7.42 (m, 2H), 7.39-7.29 (m, 4H), 7.26-7.22 (m,
2H), 7.19 (d, J = 8.4 Hz, 2H), 3.22 (t, J = 7.7 Hz, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.37 (t, J = 7.3
Hz, 2H), 2.32 (s, 3H), 1.58-1.52 (m, 2H), 1.34-1.26 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 209.7, 144.9, 136.6, 136.5, 135.5, 132.7, 130.5, 129.8 (2C), 128.7, 127.6,
126.4, 124.7, 124.3, 123.9, 119.5, 115.2, 43.7, 42.4, 26.0, 22.3, 21.6, 21.3, 13.9. HRMS (EI+)
calcd. for C28H29NO3S [M]+: 459.1868, measured: 459.1867.
N-tosyl-2-(3-oxo-3-cyclopentylpropyl)-3-phenylindole (3ac): 175 mg (93%), yellow oil,
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eluent: hexanes/EtOAc = 7/1; Rf = 0,36 (hexanes/EtOAc = 4/1). H NMR (500 MHz, CDCl3) δ
8.27 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.45-7.42 (m, 2H), 7.38-7.28 (m, 5H), 7.24-
7.22 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 3.24 (t, J = 7.7 Hz, 2H), 2.96 (t, J = 7.7 Hz, 2H), 2.85
(pent, J = 8.4 Hz, 1H), 2.34 (s, 3H), 1.84-1.70 (m, 4H), 1.68-1.54 (m, 4H). 13C NMR (125 MHz,
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CDCl3) δ 211.6, 144.8, 136.7, 136.7, 135.7, 132.8, 130.6, 129.8, 129.8, 128.7, 127.6, 126.4,
124.6, 124.2, 123.8, 119.5, 115.2, 51.3, 42.8, 28.8, 26.0, 21.5, 21.4. HRMS (EI+) calcd. for
C29H29NO3S [M]+: 471.1868, measured: 471.1877.
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N-tosyl-2-(3-oxo-3-cyclohexylpropyl)-3-phenylindole (3ad): 146 mg (75%), yellow oil,
eluent: hexanes/EtOAc = 9/1; Rf = 0,41. 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.4 Hz, 1H),
7.64 (d, J = 8.0 Hz, 2H), 7.45-7.42 (m, 2H), 7.38-7.27 (m, 5H), 7.26-7.21 (m, 1H), 7.19 (d, J =
8.0 Hz, 2H), 3.21 (t, J = 7.7 Hz, 2H), 2.94 (t, J = 7.7 Hz, 2H), 2.34 (s, 3H), 1.85-1.75 (m, 4H),
1.66-1.64 (m, 1H), 1.34-1.17 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 212.5, 144.8, 136.8, 136.7,
135.6, 132.7, 130.6, 129.8, 129.7, 128.6, 127.6, 126.4, 124.6, 124.2, 123.8, 119.4, 115.2, 50.7,
41.7, 28.5, 25.9, 25.7, 21.5, 21.3. HRMS (ES+) calcd. for C30H32NO3S [M+H]+: 486.2103,
measured 486.2081.
N-tosyl-2-(3-phenyl-3-oxopropyl)-3-phenylindole (3ae): 166 mg (87%), yellow oil, eluent:
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hexanes/EtOAc = 9/1; Rf = 0,38. H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 9.7 Hz, 1H), 7.95-
7.93 (m, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.45-7.42 (m, 4H), 7.38-7.31 (m, 5H),
7.25-7.19 (m, 3H), 3.49-3.42 (m, 4H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.6, 144.9,
136.8, 136.6, 136.5, 135.6, 133.0, 132.7, 130.6, 129.9, 129.8, 128.7, 128.5, 128.1, 127.7, 126.4,
124.7, 124.5, 123.9, 119.5, 115.2, 40.1, 21.8, 21.5. HRMS (ES+) calcd. for C30H25NO3S
[M+H]+: 480.1633, measured: 480.1638.
N-tosyl-2-[3-(2-methoxyphenyl)-3-oxopropyl]-3-phenylindole (3af): 173 mg (85%), colorless
1
oil, eluent: hexanes/EtOAc = 5/1; Rf = 0,24. H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz,
1H), 7.74-7.72 (m, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.44-7.42 (m, 3H), 7.36-7.32 (m, 5H), 7.24-
7.22 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.01-6.92 (m, 2H), 3.84 (s, 3H), 3.49 (t, J = 7.1 Hz, 2H),
3.41 (t, J = 7.1 Hz, 2H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 200.4, 158.8, 144.7, 137.2,
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136.7, 135.8, 133.4, 132.9, 130.7, 130.4, 129.9 (2C), 129.7 (2C), 128.7 (2C), 127.8, 127.5, 126.4
(2C), 124.5, 124.1, 123.8, 120.5, 119.4, 115.2, 111.5, 55.5, 45.0, 21.8, 21.5. HRMS (EI+) calcd.
for C31H27NO4S [M]+: 509.1661, measured: 509.1663.
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N-tosyl-2-[3-(2-trifluoromethylphenyl)-3-oxopropyl]-3-phenylindole (3ag): 122 mg (56%),
colorless oil, eluent: hexanes/EtOAc = 7/1; Rf = 0,26. 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J =
8.4 Hz, 1H), 7.71-7.69 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.61-7.58 (m, 1H), 7.56-7.50 (m, 2H),
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7.47-7.44 (m, 2H), 7.41-7.29 (m, 5H), 7.24-7.20 (m, 3H), 3.43-3.36 (m, 4H), 2.35 (s, 3H); C
NMR (125 MHz, CDCl3) δ 202.7, 144.9, 139.9, 136.7, 135.8, 135.6, 132.5, 131.8, 130.5, 130.0,
129.9, 129.7, 128.7, 127.8, 127.1, 126.9 (q, JC-F = 32.4 Hz), 126.6 (q, JC-F = 4.4 Hz), 126.4,
124.8, 124.6, 123.9, 123.6 (q, JC-F = 272.5 Hz), 119.6, 115.1, 44.4, 21.6, 21.4. HRMS (EI+)
calcd. for C31H24NO3SF3 [M]+: 547.1429, measured: 547.1435.
N-tosyl-2-[3-(naphthyl-1)-3-oxopropyl]-3-phenylindole (3ah): 112 mg (53%), yellow oil,
eluent: hexanes/EtOAc = 7/1; Rf = 0,28. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J = 8.4 Hz, 1H),
8.29 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90-7.86 (m, 2H), 7.69 (d, J = 8.0 Hz, 2H),
7.59-7.51 (m, 2H), 7.48-7.43 (m, 3H), 7.40-7.32 (m, 5H), 7.25-7.22 (m, 1H), 7.20 (d, J = 8.0 Hz,
2H), 3.53-3.49 (m, 4H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 202.8, 144.9, 136.8, 136.5,
135.7, 135.5, 133.9, 133.2, 132.9, 132.7, 132.6, 130.5, 130.1, 129.8, 128.8, 128.4, 127.8, 127.7,
126.4, 126.3, 125.8, 124.7, 124.5, 124.4, 123.9, 119.5, 115.2, 43.3, 22.1, 21.5. HRMS (ES+)
calcd. for C34H27NO3S [M+H]+: 530.1790, measured: 530.1791.
N-tosyl-2-[3-(2,4,6-tri-iso-propylphenyl)-3-oxopropyl]-3-phenylindole (3ai): 116 mg (48%),
colorless oil, eluent: hexanes/EtOAc = 9/1; Rf = 0,33. 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J =
8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.48-7.39 (m, 3H), 7.34-7.31 (m, 4H), 7.23-7.20 (m, 3H),
6.98 (s, 2H), 3.45 (t, J = 7.5 Hz, 2H), 3.25 (t, J = 7.5 Hz, 2H), 2.88 (sept, J = 6.6 Hz, 1H), 2.60
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(sept, J = 6.6 Hz, 2H), 2.36 (s, 3H), 1.25 (d, J = 6.6 Hz, 6H), 1.20 (d, J = 6.6 Hz, 12H); 13C NMR
(125 MHz, CDCl3) δ 209.4, 149.4, 144.8, 143.6, 137.5, 136.6, 136.3, 135.8, 132.9, 130.5, 129.9,
129.8, 128.7, 127.7, 126.4, 124.6, 124.4, 123.8, 121.0, 119.4, 115.1, 47.7, 34.3, 30.9, 24.5, 24.0,
21.6, 21.1. HRMS (EI+) calcd. for C39H43NO3S [M]+: 605.2964, measured: 605.2958.
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N-tosyl-2-[3-(4-trifluoromethylphenyl)-3-oxopropyl]-3-phenylindole (3aj): 131 mg (60%),
colorless oil; eluent: hexanes/EtOAc = 9/1; Rf = 0,23. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J =
8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H) 7.45-7.42
(m, 2H), 7.39-7.30 (m, 5H), 7.25-7.22 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 3.51-3.43 (m, 4H), 2.34
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.7, 145.0, 139.2, 136.8, 136.0, 135.5, 134.3 (q, JC-F
=
32.4 Hz), 132.6, 130.5, 129.9, 129.8, 128.8, 128.4, 127.8, 126.4, 125.6 (q, JC-F = 3.0 Hz), 124.9,
124.8, 124.0, 123.7 (q, JC-F = 272.7 Hz), 119.6, 115.2, 40.4, 21.8, 21.5. HRMS (EI+) calcd. for
C31H24NO3SF3 [M]+: 547.1429, measured: 547.1437.
N-tosyl-2-[3-(4-fluorophenyl)-3-oxopropyl]-3-phenylindole (3ak): 165 mg (83%), light blue
oil; eluent: hexanes/EtOAc = 7/1; Rf = 0,31. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz,
1H), 7.98-7.95 (m, 2H), 7.67 (d, J = 7.7 Hz, 2H), 7.45-7.42 (m, 2H), 7.38-7.31 (m, 5H), 7.25-
7.19 (m, 3H), 7.11-7.08 (m, 2H), 3.44 (s, 4H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
197.0, 165.7 (d, JC-F = 255 Hz), 144.9, 136.8, 136.4, 135.6, 133.1, 132.6, 130.7 (d, JC-F = 9.25
Hz), 130.5 , 129.9, 129.8, 128.8, 127.7, 126.4, 124.6, 124.4 (d, JC-F = 105 Hz), 119.6, 115.7,
115.5, 115.2, 40.0, 21.8, 21.5. HRMS (EI+) calcd. for C30H24NO3SF [M]+: 497.1461, measured:
497.1455.
N-tosyl-2-[3-(4-bromophenyl)-3-oxopropyl]-3-phenylindole (3al): 156 mg (70%), colorless
oil, eluent: hexanes/EtOAc = 7/1; Rf = 0,28. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.0 Hz,
1H), 7.80 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.45-7.45 (m,
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2H), 7.39-7.30 (m, 5H), 7.25-7.19 (m, 3H), 3.43 (s, 4H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.6, 144.9, 136.8, 136.2, 135.5, 135.3, 132.6, 131.8, 130.5, 129.9, 129.8, 129.6,
128.8, 128.2, 127.7, 126.4, 124.8, 124.7, 123.9, 119.6, 115.2, 40.0, 21.8, 21.5. HRMS (ES+)
calcd. for C30H24NO3SBr [M+H]+: 558.0739, measured: 558.0742.
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N-tosyl-2-[3-(4-methoxyphenyl)-3-oxopropyl]-3-phenylindole (3am): 114 mg (56%),
colorless oil, eluent: hexanes/EtOAc = 4/1; Rf = 0,33. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J =
9.1 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.68-7.66 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.29 (m, 5H),
7.24-7.21 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.91-6.89 (m, 2H), 3.86 (s, 3H), 3.41 (s, 4H), 2.34
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(s, 3H); C NMR (125 MHz, CDCl3) δ 197.2, 163.4, 144.8, 136.8, 132.7, 130.6, 130.3, 129.9,
129.5, 128.9, 128.7, 128.0, 127.6, 126.4, 125.9, 124.7, 124.3, 123.9, 119.5, 115.2, 113.6, 55.4,
39.8, 21.9, 21.5. HRMS (ES+) calcd. for C31H28NO4S [M+H]+: 510.1739, measured: 510.1741.
N-tosyl-2-[3-oxo-5-(etoxycarbonyl)pentyl]-3-phenylindole (3an): 123 mg (61%), yellow oil,
eluent: hexanes/EtOAc = 5/1; Rf = 0,20. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 9.7 Hz, 1H),
7.64 (d, J = 8.4 Hz, 2H), 7.45-7.42 (m, 2H), 7.38-7.27 (m, 5H), 7.23-7.18 (m, 3H), 4.12 (q, J =
7.0 Hz, 2H), 3.26 (t, J = 7.7 Hz, 2H), 2.96 (t, J = 7.7 Hz, 2H), 2.73 (t, J = 6.6 Hz, 2H), 2.58 (t, J
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= 6.6 Hz, 2H), 2.34 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3) δ 207.3,
172.6, 144.8, 136.7, 136.3, 135.6, 132.6, 130.5, 129.8, 129.7, 128.7, 127.7, 126.3, 124.7, 124.4,
123.9, 119.5, 115.2, 60.6, 43.7, 36.9, 28.0, 21.5, 21.5, 14.2. HRMS (EI+) calcd. for C29H29NO5S
[M]+: 503.1766, measured: 503.1759.
N-tosyl-2-[3-oxo-5-(cyclohexyloxycarbonyl)pentyl]-3-phenylindole (3ao): 189 mg (68%),
colorless oil, eluent: hexanes/EtOAc = 7/1; Rf = 0,21. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J =
8.0 Hz, 1H), 7.65-7.63 (m, 2H), 7.45-7.42 (m, 2H), 7.39-7.36 (m, 1H), 7.34-7.26 (m, 4H), 7.23-
7.17 (m, 3H), 4.74 (sept, J = 4.2 Hz, 1H), 3.28-3.24 (m, 2H), 2.98-2.94 (m, 2H), 2.73 (t, J = 6.7
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Hz, 2H), 2.56 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 1.83-1.80 (m, 2H), 1.73-1.68 (m, 2H), 1.55-1.50
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(m, 1H), 1.44-1.22 (m, 5H); C NMR (100 MHz, CDCl3) δ 207.3, 172.1, 144.9, 136.7, 136.3,
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135.6, 132.6, 130.5, 129.8, 129.8, 128.7, 127.7, 126.4, 124.7, 124.4, 123.9, 119.5, 115.2, 72.9,
43.7, 37.1, 31.5, 28.4, 25.3, 23.7, 21.6, 21.3. HRMS (EI+) calcd. for C30H35NO5S [M]+:
557.2236, measured: 557.2243.
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N-tosyl-2-(2-methyl-3-oxobutyl)-3-phenylindole (3ap): 150 mg (87%), yellow oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,31. 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 7.61 (d,
J = 8.0 Hz, 2H), 7.45-7.42 (m, 2H), 7.39-7.27 (m, 5H),7.23-7.20 (m, 1H), 7.18 (d, J = 8.0 Hz,
2H), 3.47 (dd, J = 14.4, 4.4 Hz, 1H), 3.32-3.25 (m, 1H), 2.97 (dd, J = 14.4, 9.5 Hz, 1H), 2.33 (s,
3H), 2.13 (s, 3H), 0.82 (d, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 211.8, 144.8, 137.0,
135.3, 135.1, 132.7, 130.8, 130.2, 129.7, 128.7, 127.7, 126.8, 126.3, 124.8, 124.1, 119.6, 115.5,
47.5, 29.4, 28.5, 21.5, 15.4. HRMS (EI+) calcd. for C26H25NO3S [M]+: 431.1555, measured:
431.1559.
N-tosyl-2-[(2-oxocyclohexyl)methyl]-3-phenylindole (3aq): 128 mg (70%), yellow oil,
eluent: hexanes/EtOAc = 7/1; Rf = 0,16. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 8.7 Hz, 1H),
7.62 (d, J = 8.2 Hz, 2H), 7.44-7.40 (m, 2H), 7.35-7.26 (m, 3H), 7.25-7.16 (m, 5H), 3.65 (dd, J =
14.6, 3.5 Hz, 1H), 3.08-3.00 (m, 1H), 2.89 (dd, J = 14.6, 9.9 Hz, 1H), 2.33 (s, 3H), 2.34-2.31 (m,
2H), 2.05-1.99 (m, 1H), 1.81-1.76 (m, 1H), 1.68-1.65 (m, 1H), 1.59-1.48 (m, 2H), 0.90-0.83 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 212.0, 144.8, 137.0, 135.6, 135.2, 133.0, 130.8, 130.2,
129.7, 128.6, 127.6, 126.6, 126.4, 124.6, 124.0, 119.4, 115.5, 51.2, 42.0, 32.7, 27.8, 26.7, 25.1,
21.5. HRMS (EI+) calcd. for C28H27NO3S [M]+: 457.1712, measured: 457.1716.
N-tosyl-2-(2-hydroxyphenylmethyl)-3-phenylindole (3ar): 82 mg (45%), colorless oil, eluent:
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hexanes/EtOAc = 7/1; Rf = 0,39. H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.46-
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7.33 (m, 9H), 7.27-7.25 (m, 1H), 7.08-7.03 (m, 3H), 6.80-6.65 (m, 3H), 5.53 (s, 1H), 4.45 (s,
2H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 153.0, 144.6, 136.7, 135.6, 134.7, 132.7,
130.2, 129.8 129.6, 129.6, 126.4, 128.8, 127.7, 127.4, 126.5, 126.1, 124.8, 123.7, 120.9, 119.7,
116.2, 115.1, 26.0, 21.5. HRMS (EI+) calcd. for C28H23NO3S [M]+: 453.1399, measured:
453.1407.
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2-N-Tosylaminophenyl(phenyl)(menthofuryl-2)methane (4as): 184 mg (95%), colorless oil,
eluent: hexanes/EtOAc = 9/1; Rf = 0,39. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 2H),
7.48 (d, J = 7.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.24-7.20 (m, 3H), 7.06 (dd, J = 8.1, 7.0 Hz, 1H),
6.81-6.78 (m, 3H), 6.43 (d, J = 7.0 Hz, 1H), 4.88 (d, J = 4.0 Hz, 1H), 2.60-2.52 (m, 1H), 2.43 (s,
3H), 2.37-2.27 (m, 2H), 2.13-2.05 (m, 1H), 1.91-1.79 (m, 2H), 2.66 (d, J = 4.0 Hz, 3H), 1.38-
1.26 (m, 2H), 1.05 (d, J = 7.0 Hz, 3H), 1.01-0.84 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 150.0,
145.4, 143.8, 140.1, 137.0, 135.4, 135.3, 134.4, 129.7, 128.7, 128.6, 127.7, 127.1, 126.9, 126.0,
124.9, 124.8, 118.2, 116.5, 44.7, 31.4, 31.2, 29.6, 21.5, 20.1, 7.9. HRMS (EI+) calcd. for
C30H31NO3S [M]+: 485.2025, measured: 485.2015.
N-tosyl-2-(3-oxobutyl)-3-methylindole (3ba): 125 mg (88%), colorless oil, eluent:
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hexanes/EtOAc = 7/1; Rf = 0,31. H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.57-
7.56 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.31-7.23 (m, 2H), 7.15-7.14 (m, 2H), 3.23-3.20 (m, 2H),
2.94-2.91 (m, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 207.7,
144.5, 136.6, 135.6, 135.4, 131.4, 129.7, 126.2, 124.3, 123.5, 118.5, 117.6, 115.0, 43.9, 29.9,
21.5, 20.7, 8.9. HRMS (ES+) calcd for C20H22NO3S [M+H]+: 356.1320, measured: 356.1323.
N-tosyl-2-(3-oxobutyl)-3-isopropylindole (3ca): 117 mg (76%), colorless oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,35. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H), 7.59 (d,
J = 7.7 Hz, 1H), 7.55-7.53 (m, 2H), 7.26 (m, 1H), 7.21 (m, 1H), 7.16-7.14 (m, 2H), 3.24-3.20
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(m, 2H), 3.14 (sept, J = 7.0 Hz, 1H), 2.90-2.87 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 1.32 (d, J =
7.2 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 207.7, 144.5, 137.2, 135.7, 134.2, 129.7, 129.2,
127.3, 126.2, 123.8, 123.0, 120.2, 115.4, 44.6, 30.0, 25.9, 22.1, 21.5, 20.8. HRMS (ES+) calcd
for C22H26NO3S [M+H]+: 384.1633, measured: 384.1636.
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N-tosyl-2-(3-oxobutyl)-3-tertbutylindole (3da): 100 mg (63%), colorless oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,33 (hexanes/EtOAc = 4/1). 1H NMR (500 MHz, CDCl3) δ 8.28 (d,
J = 8.4 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.49-7.48 (m, 2H), 7.24 (m, 1H), 7.19 (m, 1H), 7.15-
7.14 (m, 2H), 3.45-3.42 (m, 2H), 2.91 (broad s, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.46 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 207.6, 144.5, 137.7, 135.7, 135.0, 130.3, 129.6, 129.0, 126.1, 123.7,
122.9, 122.3, 115.8, 45.4, 34.0, 31.6, 29.9, 21.6, 21.5. HRMS (ES+) calcd for C23H28NO3S
[M+H]+: 398.1790, measured: 398.1797.
N-tosyl-2-(3-oxobutyl)-3-cyclohexylindole (3ea): 141 mg (83%), colorless oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,36 (hexanes/EtOAc = 4/1). 1H NMR (500 MHz, CDCl3) δ 8.21 (d,
J = 8.3 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.54-7.52 (m, 2H), 7.24 (t, J = 8.3 Hz, 1H), 7.19 (t, J =
7.9 Hz, 1H), 7.15-7.13 (m, 2H), 3.25-3.22 (m, 2H), 2.90-2.87 (m, 2H), 2.72 (m, 1H), 2.31 (s,
3H), 2.18 (s, 3H), 1.90-1.77 (m, 5H), 1.61-1.59 (m, 2H), 1.42-1.26 (m, 3H). 13C NMR (125
MHz, CDCl3) δ 207.8, 144.5, 137.2, 135.7, 124.6, 129.7, 126.6, 126.2, 123.8, 123.0, 120.5,
115.3, 44.7, 36.7, 32.0, 30.0, 26.9, 26.1, 21.5, 20.8. HRMS (ES+) calcd for C25H30NO3S
[M+H]+: 424.1946, measured: 424.1944.
N-tosyl-2-(3-oxobutyl)-3-(4-fluorophenyl)indole (3fa): 126 mg (72%), yellow oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,23 (hexanes/EtOAc = 4/1). 1H NMR (500 MHz, CDCl3) δ 8.26 (d,
J = 8.4 Hz, 1H), 7.65-7.64 (m, 2H), 7.33 (t, J = 8.3 Hz, 1H), 7.28-7.22 (m, 4H), 7.20-7.19 (m,
2H), 7.14 (d, J = 8.6 Hz, 2H), 3.24-3.20 (m, 2H), 2.95-2.91 (m, 2H), 2.34 (s, 3H), 2.14 (s, 3H).
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13C NMR (125 MHz, CDCl3) δ 207.1, 162.3 (d, JC-F = 247.8 Hz), 145.0, 136.6, 136.5, 135.5,
131.5 (d, JC-F = 7.4 Hz), 130.5, 129.9, 128.6 (d, JC-F = 2.8 Hz), 126.4, 124.4 (d, JC-F = 105.4 Hz),
123.4, 119.3, 115.9, 115.7, 115.2, 44.6, 29.7, 21.6, 21.2. HRMS (ES+) calcd for C25H23FNO3S
[M+H]+: 436.1383, measured: 436.1376.
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N-tosyl-2-(3-oxobutyl)-3-(4-methylphenyl)indole (3ga): 103 mg (60%), yellow oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,25 (hexanes/EtOAc = 4/1). 1H NMR (500 MHz, CDCl3) δ 8.26 (d,
J = 9.0 Hz, 1H), 7.65-7.64 (m, 2H), 7.33-7.31 (m, 2H), 7.28-7.26 (m, 2H), 7.23 (m, 1H), 7.20-
7.18 (m, 4H), 3.24-3.20 (m, 2H), 2.95-2.91 (m, 2H), 2.42 (s, 3H), 2.34 (s, 3H), 2.14 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 207.3, 144.8, 137.4, 136.6, 136.1, 135.5, 130.6, 129.8, 129.6, 129.5,
129.4, 126.3, 124.6, 124.4, 123.8, 119.5, 115.1, 44.7, 29.7, 21.5, 21.3, 21.2. HRMS (EI+) calcd
for C26H25NO3S [M]+: 431.1555, measured: 431.1561.
N-tosyl-2-(3-oxobutyl)-3-(4-methoxyphenyl)indole (3ha): 127 mg (71%), yellow oil, eluent:
hexanes/EtOAc = 7/1; Rf = 0,19 (hexanes/EtOAc = 4/1). 1H NMR (500 MHz, CDCl3) δ 8.25 (d,
J = 8.8 Hz, 1H), 7.65-7.63 (m, 2H), 7.33-7.30 (m, 2H), 7.21-7.17 (m, 5H), 6.99-6.97 (m, 2H),
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3.85 (s, 3H), 3.26-3.23 (m, 2H), 2.95-2.92 (m, 2H), 2.33 (s, 3H), 2.13 (s, 3H). C NMR (125
MHz, CDCl3) δ 207.3, 159.1, 144.8, 136.6, 136.0, 135.5, 130.9, 130.8, 129.8, 126.3, 124.7,
124.6, 124.1, 123.8, 119.4, 115.1, 114.2, 55.2, 44.6, 29.7, 21.5, 21.3. HRMS (EI+) calcd for
C26H25NO4S [M]+: 447.1504, measured: 447.1509.
N-tosyl-2-(3-oxobutyl)-3-(thiophen-2-yl)indole (3ia): 69 mg (41%), yellow oil, eluent:
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hexanes/EtOAc = 7/1; Rf = 0,22 (hexanes/EtOAc = 4/1). H NMR (500 MHz, CDCl3) δ 8.25 (d,
J = 8.4 Hz, 1H), 7.67-7.65 (m, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.39 (dd, J = 5.3, 0.7 Hz, 1H), 7.34
(m, 1H), 7.26 (m, 1H), 7.21-7.20 (m, 2H), 7.14 (m, 1H), 7.05 (dd, J = 3.5, 0.7 Hz, 1H), 3.36-3.33
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(m, 2H), 3.00-2.97 (m, 2H), 2.34 (s, 3H), 2.18 (s, 3H). C NMR (125 MHz, CDCl3) δ 207.1,
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145.1, 137.6, 136.3, 135.6, 133.1, 130.1, 129.9, 127.5, 127.4, 126.4, 126.0, 124.9, 124.0, 119.6,
116.8, 115.0, 44.7, 29.8, 21.6, 21.4. HRMS (ES+) calcd for C23H22NO3S2 [M+H]+: 424.1041,
measured: 424.1042.
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N-tosyl-2-(3-oxobutyl)-3-phenyl-5,6-difluoroindole (3ja): 143 mg (79%), colorless solid,
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eluent: hexanes/EtOAc = 7/1; Rf = 0,27 (hexanes/EtOAc = 4/1). H NMR (500 MHz, CDCl3) δ
8.12 (dd, J = 11.4, 7.0 Hz, 1H), 7.64-7.62 (m, 2H), 7.46-7.43 (m, 2H), 7.38 (m, 1H), 7.25-7.22
(m, 4H), 7.12 (dd, J = 9.9, 7.9 Hz, 1H), 3.21-3.18 (m, 2H), 2.93-2.90 (m, 2H), 2.37 (s, 3H), 2.13
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(s, 3H). C NMR (125 MHz, CDCl3) δ 206.9, 148.8 (ddd, JC-F = 244.1, 19.4, 14.8 Hz), 145.4,
137.6 (d, JC-F = 4.6 Hz), 135.1, 131.9, 131.6, 131.6, 130.0, 129.5, 128.9, 128.0, 126.3, 123.8,
107.6 (d, JC-F = 19.4 Hz), 104.5 (d, JC-F = 24.0 Hz), 44.5, 29.7, 21.6, 21.3. HRMS (ES+) calcd
for C25H22NO3SF2 [M+H]+: 454.1288, measured: 454.1291.
N-tosyl-2-(3-oxobutyl)-3-phenyl-5,6-dimethoxyindole (3ka): 114 mg (60%), yellow solid,
eluent: hexanes/EtOAc = 3/1; Rf = 0,19. The spectral data matched that of the previously
synthesized material.6 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.59-7.57 (m, 2H), 7.46-7.43
(m, 2H), 7.37 (m, 1H), 7.26-7.25 (m, 2H), 7.19-7.17 (m, 2H), 6.72 (s, 1H), 4.00 (s, 3H), 3.79 (s,
3H), 3.19-3.16 (m, 2H), 2.93-2.90 (m, 2H), 2.33 (s, 3H), 2.12 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 207.3, 147.8, 147.4, 144.7, 135.3, 134.8, 132.8, 130.7, 129.7, 129.6, 128.7, 127.6,
126.1, 124.7, 123.5, 100.8, 99.3, 56.4, 56.0, 44.7, 29.7, 21.5, 21.4. HRMS (ES+) calcd for
C27H28NO5S [M+H]+: 478.1688, measured: 478.1679.
N-tosyl-2-(3-oxobutyl)-3-phenyl-6-trifluoromethylindole (3la): 122 mg (63%), colorless
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solid, eluent: hexanes/EtOAc = 7/1; Rf = 0,24 (hexanes/EtOAc = 4/1). H NMR (500 MHz,
CDCl3) δ 8.57 (d, J = 0.7 Hz, 1H), 7.67-7.65 (m, 2H), 7.48-7.45 (m, 3H), 7.42-7.38 (m, 2H),
7.28-7.23 (m, 4H), 3.28-3.25 (m, 2H), 2.95-2.92 (m, 2H), 2.36 (s, 3H), 2.14 (d, J = 1.3 Hz, 3H).
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